Azithromycin is a well-known semi-synthethic macrolide antibiotic (U.S. Pat. Nos. 4,474,768 and 4,517,358), which is prepared through the expansion/inclusion of a nitrogen atom in the macrolide ring of erythromycin A, followed by reductive methylation. In this way, an antibiotic more stable and more effective than erythromycin A is obtained, particularly against gram-negative bacteria.
The reaction sequence to transform erythromycin A into azithromycin involves extremely strong and aggressive reaction conditions (compare, J. Chem. Soc. Perkin Trans. I, 1881 (1986)), and requires the isolation of intermediates, which, in certain conditions, are even more unstable than the starting material. Reaction conditions and isolation procedures must be at the same time both mild and have their parameters strictly controlled. This can result in additional problems when a laboratory scale process is put into practice at an industrial level. Under these circumstances, additional restrictions on the manufacturing process have to be implemented in order to ensure that azithromycin is obtained in good yield and high purity.
The transformation of erythromycin A into azithromycin involves: conversion of erythromycin into its oxime; Beckmann rearrangement of the oxime to produce the imino ether of erythromycin A; reduction of the imino ether to 9-deoxo-9a-aza-9a-homoerythromycin, and, finally, reductive N-methylation to obtain the final product.
The reduction of the imino ether and reductive methylation have so far been described as a two-step process (PCT Patent Application No. 94/02547-Publication No. 94/26758; European Patent No. 0 109 253), presumably because in these procedures, purification of the 9-deoxo-9a-aza-9a-homoerythromycin is required before proceeding to the next step.
According to the present invention, it has been found that a suitable imino ether of erythromycin can be reduced, and the product thus obtained can be subsequently submitted to reductive methylation in the presence of the same noble metal catalyst and in the presence of formaldehyde or a source thereof, without any isolation of the intermediate product. The two reactions already known per se can subsequently be conducted using the same catalytic system in the same reaction vessel and in the same reaction medium. By carefully choosing the reaction conditions, one can obtain a product of good purity and with a good yield. Thus, the present process represents a considerable industrial advantage over the prior art by reducing the number of reactors and manipulations, like the isolation of the intermediate product. The preferred reaction conditions are described hereinafter.
According to the previously published literature, the conditions which have been found to be most effective to carry out the reduction of the imino ether are: utilisation of reducing agents in stoichiometric amounts or high pressure hydrogenation using platinum (PCT Patent Application No. 94/02547-Publication No. 94/26758).
This is then followed by isolating cyclic amine, which is then subject to reductive methylation, employing the well-known Eschweiler-Clarke conditions--formaldehyde and formic acid in chloroform--or by hydrogenation--formaldehyde and hydrogen in the presence of a noble metal catalyst (U.S. Pat. No. 4,517,359, J. Chem. Res., 1988, 1239-1261).
The reduction by sodium borohydride (EU Patent No. 0109253, J. Chem Soc. Perkin Trans., I, 1986, 1881) involves an extremely exacting procedure as far as completion of the reaction and recovery of the product are concerned. The initial intermediate present in the reaction medium is apparently a boron containing complex, which must be destroyed in order that the 9-deoxo-9-a-aza-9a-homoerythromycin can be isolated. The complex in question must be eliminated under acid conditions and since, as is known, the macrolide in question is sensitive to acid media, the conditions for this step must be rigorously controlled.
This procedure becomes more problematic at the industrial scale, since the times of contact between the sensitive intermediate and the undesired aqueous acid medium are inevitably more prolonged.